Pharmacology & Therapeutics 170 (2017) 14–36 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Associate editor: N. Frossard New therapeutic opportunities for 5-HT2 receptor ligands Luc Maroteaux b,1, Estelle Ayme-Dietrich a,1, Gaëlle Aubertin-Kirch a, Sophie Banas b, Emily Quentin b, Roland Lawson a, Laurent Monassier a,⁎ a Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire EA7296, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg, Université et Centre Hospitalier de Strasbourg, Strasbourg, France b INSERM UMR S-839, Institut du Fer à Moulin, Université Pierre et Marie Curie, 17 rue du Fer à Moulin 75005, Paris, France article info abstract Available online 19 October 2016 Serotonergic dysfunction is mainly associated with neuropsychiatric and cardiovascular disorders but has also been linked with many other pathological conditions. Serotonin (5-hydroxytryptamine, 5-HT) mediates numer- Keywords: ous physiological functions in the brain and the periphery by activating a variety of receptors. 5-HT receptors are 5-HT2 receptors divided into four classes, three of which belong to the G protein-coupled receptor family. This review provides Selectivity an overview of the recent pharmacological developments involving the Gq-coupled 5-HT2 receptor subfamily Pathological function as well as the pathological implications of this receptor subfamily with regard to fibrosis, the central nervous Therapeutic track system, cardiovascular disorders, and cancer. The final section highlights new therapeutic opportunities and emerging research revealing unexplored medical opportunities for this class of 5-HT receptors. The development of biased 5-HT2 receptor ligands appears to be an interesting topic in various areas. In light of recent discoveries, the need for the development of new and safer drugs should take into account the risk of cardiovascular side effects such as pulmonary hypertension and heart valve disease. © 2016 Elsevier Inc. All rights reserved. Contents 1. Introduction.............................................. 14 2. 5-HT2 receptors: structure, coupling, oligomerization, selective ligands, allosteric modulators, biased agonists . 15 3. Pathologies and 5-HT2 receptors..................................... 18 4. Emergingresearchandnewtherapeuticopportunities........................... 28 5. Conclusionsandprospects........................................ 31 Conflictofinterest.............................................. 31 Acknowledgments.............................................. 31 References.................................................. 31 1. Introduction et al. (1988) was the first to report the cloning of a full-length functional serotonin receptor from rat (the 5-HT1c receptor), this publication was This review focuses on three serotonin (5-hydroxytryptamine, shortly followed by considerable efforts from several groups that cloned 5-HT) receptors belonging to the 5-HT2 receptor subfamily: the other unidentified 5-HT receptors. The classical 5-HT2 receptor de- 5-HT2A, 5-HT2B, and 5-HT2C subtypes. Although the work by Julius scribed by Peroutka et al. (1981) was cloned from rats slightly later in 1988 (Pritchett et al., 1988) followed by human analogue (Branchek et al., 1990; Saltzman et al., 1991) and was renamed 5-HT2A.The 5-HT1c receptor was renamed 5-HT2C because of its structural similarity ⁎ Corresponding author at: LaboratoiredeNeurobiologieetPharmacologie to the other 5-HT2 receptor, identical second messenger pathways, and Cardiovasculaire, Faculté de Médecine, Université et Centre Hospitalier de Strasbourg, similar pharmacological properties. Pharmacological studies attempting 11 rue Humann, 67085 Strasbourg, France. Tel.: +33 368853392; fax: +33 368853388. to characterize the contractile serotonergic receptor in the rat stomach E-mail address: [email protected] (L. Monassier). 1 Luc Maroteaux and Estelle Ayme-Dietrich contributed equally to this review and are fundus initially documented its similarity to the 5-HT2C receptor. considered co-authors. Despite the absence of detectable 5-HT2C receptor mRNA in the rat http://dx.doi.org/10.1016/j.pharmthera.2016.10.008 0163-7258/© 2016 Elsevier Inc. All rights reserved. L. Maroteaux et al. / Pharmacology & Therapeutics 170 (2017) 14–36 15 stomach fundus, only homology cloning permitted the identification of 2.2. Selective agonists a new receptor in 1992 in rat and mouse that was named 5-HT2B (Foguet et al., 1992a, 1992b; Kursar et al., 1992; Loric et al., 1992; There is virtually no highly selective agonist for a particular 5-HT2 Wainscott et al., 1993) and in 1994 in humans (Choi et al., 1994; receptor: Kursar et al., 1994; Schmuck et al., 1994; Wainscott et al., 1996). - BW723C86: 1-methyl-2-[5-(2-thienylmethoxy)-1H-indole-3-yl] The investigation of the contribution of these three 5-HT2 receptors ethylamine hydrochloride has been reported to have 10-fold selec- in mammalian physiology has led to a large number of reports in nearly tivity over the human 5-HT and 100-fold selectivity over the all functions and organs. Some selective compounds stimulating or 2C 5-HT receptors (Porter et al., 1999; Jerman et al., 2001; Knight blocking these receptors provided an opportunity to explore various 2A et al., 2004; Cussac et al., 2008). Lorcaserin [(1R)-8-chloro-2,3,4,5- areas of human diseases. In this review, we will emphasize some impor- tetrahydro-1-methyl-1H-3 benzazepine] has approximately 10- tant aspects of the cellular and molecular biology of these receptors and fold higher affinity for 5-HT receptor (Thomsen et al., 2008) over highlight some clinical situations in which these receptors appear as 2C the 5-HT and 5-HT receptors. pathophysiological cornerstones. 2A 2B - Nor-dexfenfluramine (a metabolite of dexfenfluramine), methyler- gonovine (a metabolite of methysergide), and Ro 60-0175: 2(S)-1- (6-chloro-5-fluoro-1H-indol-1-yl)-2-propanamine fumarate are all 2. 5-HT2 receptors: structure, coupling, oligomerization, preferential 5-HT agonists with approximately 10-fold selectivity selective ligands, allosteric modulators, biased agonists 2B over the 5-HT2C receptor (Cussac et al., 2002). - 2,5-dimethoxy-4-iodoamphetamine (DOI) is a non-selective nearly The closely related 5-HT2 receptors are members of the rhodopsin full agonist at 5-HT receptors with similar affinity to the 5-HT , family of G protein-coupled receptors (GPCRs) that activate multiple 2 2A 5-HT ,and5-HT receptors (Porter et al., 1999; Jerman et al., intracellular signalling networks. The classical signal transduction path- 2B 2C 2001; Knight et al., 2004; Cussac et al., 2008). way for this subfamily is the Gq/11-coupled activation of phospholipase - Alpha-methyl-5-HT is a non-selective nearly full agonist at 5-HT2 C (PLC), although these 5-HT2 receptors can also activate phospholipase receptors with a similar affinity towards the 5-HT ,5-HT ,and D and phospholipase A2 by interacting with additional pathways. These 2A 2B 5-HT2C receptors (Porter et al., 1999; Jerman et al., 2001; Knight 5-HT2A, 5-HT2B, and 5-HT2C receptors are post-transcriptionally modi- et al., 2004). fied by alternative RNA splicing, a common mechanism for achieving protein diversity. RNA editing, on the other hand, is a less common pro- cess for generating molecular diversity. In fact, the 5-HT2C receptor 2.3. Selective antagonists is one of the few GPCRs known to be edited. RNA editing of the 5-HT2C receptor generates functionally distinct protein variants by altering A few selective antagonists are available for the 5-HT2 receptor the genetic code at the mRNA level. subtypes: -Thefirst highly selective 5-HT2A receptor antagonist reported 2.1. Structure was MDL100907 [(R)-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4- fluorophenylethyl)]-4-piperidine-methanol] (Knight et al., 2004). 5-HT2 receptors are 7 transmembrane domain receptors with fairly Sarpogrelate [succinic acid mono-(1-dimethylaminomethyl-2-(2- long extracellular N-terminal loops ranging from 55 amino acids for [2-(3-methoxyphenyl) ethyl] phenoxy) ethyl) ester hydrochloride], the human 5-HT2B and 5-HT2C receptors to 75 amino acids for the SR46349B [4-((3Z)-3-(2-dimethylaminoethyl)oxyimino-3-(2- human 5-HT2A receptor and an intracellular C-terminus ranging from fluorophenyl)propen-1-yl)phenol hemifumarate], and ketanserin 85 amino acids for the human 5-HT2B receptor to 75 amino acids for [3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]quinazoline-2,4(1H, the human 5-HT2A and 5-HT2C receptors. A new and unanticipated 3H)-dione] are preferential 5-HT2A receptor antagonists with a 10- role of the 5-HT2B receptor N-terminus as a negative modulator affect- fold higher affinity over the 5-HT2C and/or 5-HT2B sites. ing both constitutive and agonist-stimulated activity of the receptor - The first highly selective 5-HT2B receptor antagonist reported was has been shown (Belmer et al., 2014). The recently published crystal LY266097: 1-(2-chloro-3,4-dimethoxybenzyl)-6-methyl-1,2,3,4- structure of the 5-HT2B receptor bound to ergotamine showed that tetrahydro-9H-pyrido[3,4-b]indole hydrochloride, with a pKi of 9.7 this receptor exhibits conformational characteristics in both the active for the human cloned 5-HT2B receptor and a 100-fold greater selec- and inactive states: an active-like state in the helix VII conformation of tivity over human 5-HT2C and 5-HT2A receptors (Audia et al., 1996). the 5-HT2B receptor but only partial changes in helix VI. The differential SB204741: N-(1-methyl-5-indolyl)-N′-(3-methyl-5-isothiazolyl)